Understanding Diagnostic Testing: Is Watch-and-Wait Right for Me?

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When should I begin treatment? How long do I have to watch-and-wait? These questions are common for people living with CLL. Dr. Steven Coutre, a leading Stanford University researcher, joins our program to explain how improved testing and promising combination treatments could change the approach to front-line treatment.

This HealthTalk program is supported through an unrestricted educational grant from Berlex.

Announcer:
Welcome to this HealthTalk CLL program. Support for this program is provided through an unrestricted educational grant from Berlex. We thank them for their commitment to patient education. Before we begin, we remind you that the opinions expressed on this program are solely the views of our guests. They are not necessarily the views of HealthTalk, our sponsor or any outside organization. As always, please consult your own physician for the medical advice most appropriate for you.

Andrew Schorr:
Hello and welcome. I’m Andrew Schorr. For many years, physicians have employed a watch-and-wait approach to treating early stage CLL. I know when I was first diagnosed with CLL more than 10 years ago I was faced with many decisions as I spoke with my doctor. When should treatment begin, and should that decision be weighed with what treatment was available, and how long it might be effective? Did we want to start a clock ticking? In that case, our discussion was around the single agent fludarabine, or Fludara, and that was basically what was available at that time outside of a clinical trial.

With us today in this program, we’ll be learning if watch-and-wait continues to be the best approach to front-line treatment, and our guest is a CLL expert, Dr. Steven Coutre. Dr. Coutre is an associate professor of medicine in hematology at the Stanford University School of Medicine in Palo Alto, California. Dr. Coutre, thanks for being with us on HealthTalk.

Dr. Steven Coutre:
Thank you for inviting me.

Andrew:
Dr. Coutre, when someone is suspected of having CLL, what are the tests? What are you looking for?

Dr. Coutre:
Well, this often comes up in somebody who doesn’t necessarily have any symptoms at all. They’re having blood work done for some other reason, perhaps an annual physical, and their physician notices that their white blood cell count is elevated, mostly white cells called lymphocytes. So that’s often the first step toward establishing this diagnosis.

And although it’s a leukemia, which means it involves the bone marrow, we don’t necessarily need to do a bone marrow exam to establish the diagnosis. So you send a sample of the blood for a test called flow cytometry, and it really has a characteristic set of markers that you can detect that really establishes the diagnosis.

Andrew:
What are some of these markers?

Dr. Coutre:Well, you demonstrate that the cells are what are called B cells rather than T lymphocytes, and they have another marker called CD5 on their surface, which isn’t present on the normal B cell.

Andrew:
And my understanding of CLL is our bodies, in the bone marrow, are making too many white cells, B cells in this case, if it’s B-cell chronic lymphocytic leukemia. But they’re not effective or not mature cells. So do these look different under a microscope?

Dr. Coutre:
Not necessarily. They can look like regular lymphocytes. Sometimes they’re a bit larger. But diagnostically, one couldn’t look at that cell and say this is definitely a CLL cell. But fortunately, that testing that I mentioned very easily demonstrates that these aren’t normal B cells.

Andrew:
So you do flow cytometry. Now, as that’s progressed, have we made changes in the type of flow cytometry that you can do to tell more than just, is it B-cell CLL, but is it some subtype of CLL?

Dr. Coutre:
We haven’t had to really subtype the disease unlike, for example, some of the lymphomas. But we do have additional tests that we can do to give more information to patients as far as prognosis is concerned.

Andrew:
Tell us about those tests. One term that we’ve talked about on our programs and patients know about, although we’re not always clear on what it is, is, for instance, the FISH [fluorescence in situ hybridization] test.

Dr. Coutre:So let’s take a step back and talk about our traditional prognostic factors. That has to do with our staging system. So you probably know from many types of cancer that stage can be very important, both for choosing treatment and also prognosis.

With CLL, we have a very simple staging system that’s based on your blood counts, your physical exam, whether you have enlarged lymph nodes, for example, or an enlarged spleen. And we use this information to classify individuals from stage 0, which is the most favorable, all the way up to stage IV, which is the most advanced. And this staging system, named after Dr. Kanti Rai, has served us very well for the past several decades. It’s very simple. It doesn’t require complicated testing, and it gives a lot of information.

The problem is that the majority of individuals are like the person I described initially. They don’t have symptoms, and they fall into, let’s say, a lower stage category. And those people, obviously, want to know how they’re going to do, what’s their prognosis? So we’d like to be able to break out that group and give additional information. And that’s where some of these new prognostic tests come in.

Now, you mentioned one called FISH. So this refers to looking at the chromosome. With a lot of leukemias, chromosome abnormalities are very important in making treatment decisions, in determining prognosis. With CLL, initially, we really couldn’t find any definitive abnormalities that gave us a lot of insight into the disease, but that was based on testing that was performed on the bone marrow.

We have a newer methodology, called FISH, which we are able to use on blood cells, so we can simply use a sample of the blood without having to take a bone marrow sample. And we use very specific probes that look for very specific abnormalities. A typical panel might include four of these probes looking for abnormalities of chromosomes 11 or 13 or 12 or 17. And it gives us a lot of additional information as to how patients might do on average, both in terms of when they might need their initial treatment and also overall prognosis.

Andrew:
Okay. So at Stanford, one of the leading centers, do you routinely do FISH on an early-stage patient to then have that discussion with a patient on whether treatment should be earlier or later or what might be the course of the disease for them?

Dr. Coutre:
We generally do [run FISH tests]. I always have this discussion with the patient first, however. I explain what these tests can do, what kind of information it can give us, but I also explain that in many cases it doesn’t necessarily influence a decision to treat or not to treat. That may change, and that’s the subject of some recent clinical trials. But I think you have to have an informed discussion with your patient about what this information means before going ahead and ordering the testing.

Andrew:
Okay. Now, you mentioned some of these chromosomal differences. What about this term we hear sometimes, the mutational status of the CLL? Where does that come in, and how do you figure that out?

Dr. Coutre:So that’s another very important category in terms of prognosis. In all of us, our normal B cells go through a maturation process. They acquire certain mutations that allow them to recognize what we call antigens, things that are foreign to us, because they’re an important part of our normal immune system. So that’s a normal process.

But with CLL, you also have these B cells undergo this process, but there’s other mechanisms at play that determine their fate, that determine that these are not normal B cells but part of this leukemia. We can have mutated immunoglobulin genes in these B cells, just like normal B cells, and we can have unmutated immunoglobulin genes.

And although it may seem counterintuitive, those who are mutated, where you have a number of changes in this gene, actually have a better prognosis on average. They tend to go longer before they need treatment. Whereas, those who are unmutated tend to progress earlier and need treatment earlier.

So just like some of the chromosome abnormalities can differentiate individuals from a prognostic standpoint, this mutational status gives us another bit of information. And, in fact, the mutational status is currently thought to be probably the single best predictor of disease course, but it’s not the only predictor.

Andrew:
Is the mutational status determined by this FISH test, as well, or is it a different way?

Dr. Coutre:It is not. It is not determined by the FISH test. It’s another test done in the laboratory. But this is a more sophisticated test. This is not a test that is yet widely available. Some of the major commercial laboratories that physicians often send samples to don’t offer this. In fact, many major academic centers don’t offer this testing yet. So as we know more and more about this, however, and its importance, I think it will make its way into the routine tests that are available to physicians when they’re trying to manage their patients.

Andrew:
In the last year or two, CLL patients have been hearing this term, ZAP-70, and there are trying to be certain tests and standards that emerge for that. What is ZAP-70? What are the tests for it? Are they reliable? And then we’re going to put all of this together, if you will, Dr. Coutre, and ask, how do you make determinations on what to do?

Dr. Coutre:
This is sort of our third category. ZAP-70 is also a marker of cells, called for zeta-associated protein. Interestingly, in normals, it’s not found in the B cells, but it’s found in the T lymphocytes. But in B-cell CLL, you can see increased expression of this marker in some patients.

It was initially discovered because people were trying to find something that was easier to test that correlated with the mutational status. Since the mutation testing was more difficult, they wanted an easier test. And the ZAP-70 can be done by the flow cytometry. So one could imagine including it when you’re doing your initial testing of a patient.

The problem is, then, that it’s really not yet ready for prime time. There have been some technical difficulties in really getting robust results that you can trust. So even though this is widely available and you can order it and get a result, I think we still have to be a bit skeptical about that result. In fact, I would be hesitant to use ZAP-70 as a sole reason to start treatment in a patient, for example.

Andrew:
I want to ask you about a term we hear too, p53. What does that mean?

Dr. Coutre:
So p53 is what is called a tumor suppression gene, and we know this plays a very important role in a number of different cancers, not just CLL. It’s present on chromosome 17, and so one of the abnormalities we can detect with FISH is deletion of a portion of chromosome 17. And this happens to be where the tumor suppressor gene is located, p53. So that can sort of release a control mechanism for the disease, making it progress, making it more active, if you will. So, in fact, this absence of p53 or deletion of a portion of chromosome 17 that we can test for by FISH is considered a worse prognostic factor.

Andrew:
At [the] American Society of Clinical Oncology (ASCO) meeting - which was quite recent - you get together with the other CLL experts from around the world and you say, “Okay, we have these tests.” We have certain ones that we think give us a lot of information. When we take it all together, what do we do with the information? Do we treat some people earlier, or do we still wait until they get to a later stage?

Dr. Coutre:
The traditional approach for earlier patients, so those who don’t have symptoms at the lower stage, is based on clinical trials showing that treatment with the drugs we had available then - for example, chlorambucil, versus waiting until somebody progressed and then treating - didn’t make a difference. People didn’t live longer even if you treated them earlier. But one could argue that, well, maybe it was just because it wasn’t a particularly good drug.

So there are two factors now. We have better drugs, better combinations. And secondly, we have better testing. These prognostic factors will allow us to identify subgroups of individuals that our staging system can’t identify who would likely benefit from earlier treatment. So that, in fact, is the subject of some recently started clinical trials and a large clinical trial that will begin in the U.S. So we’ll revisit this whole issue of watch-and-wait for early stage patients who don’t have symptoms.

Everyone will be tested for these prognostic factors. And, for example, in the trial in the U.S. if a patient has the unmutated immunoglobulin profile, they’ll be eligible. They will then be randomized to use the traditional watch-and-wait approach or early treatment with the combination of two drugs that we use for treating patients with CLL.

Andrew:What are those drugs in this trial?

Dr. Coutre:
One of those is the drug you mentioned, Fludara, or fludarabine. And the second is a monoclonal antibody called rituximab. So that combination has been used to treat patients, and it’s going to be tested in this trial.

And one might imagine that perhaps it’s the patients who have some of these other abnormalities that will really benefit from this early intervention. But we need those answers, and I think, fortunately, we now have the tools to get those answers.

Andrew:Dr. Coutre, you mentioned that you now have a wider array of treatments including new approved treatments for CLL beyond chlorambucil or Leukeran. What are those? What are some of your combinations beyond the fludarabine and Rituxan [rituximab] that you’re looking at?

Dr. Coutre:
Well, we have a second monoclonal antibody called alemtuzumab that is used traditionally for patients with recurrent disease, who have failed other therapies. That’s starting to be looked at both in combination with drugs like fludarabine and also as part of earlier treatment for the disease.

We’re also starting to learn that there may be a difference in how patients respond to the different drugs that we use based on some of these tests that we’ve already discussed. For example, those who have the chromosome 17 deletion, the loss of the suppressor gene, the p53, they may respond better to some of our agents versus others.

So we’re starting to learn that we can look a little more closely at patients and be a little smarter about not only when to start therapy but also what drugs to choose based on some of these characteristics.

Andrew:
I’ll just mention to our audience we’ve also recorded an interview after this American Society of Clinical Oncology meeting with Dr. Peter Hillmen, a CLL expert from the United Kingdom, where we discussed treatment.

So given the kind of stuff that Dr. Hillmen has studied and what we’re talking about with prognostic factors, Dr. Coutre, there’s a lot more swirling around in the head of a patient. So what conversations should they have with their more generalist oncologist, on how does this apply to them?

Dr. Coutre:
I think it is worth a discussion about the prognostic factors and what they mean, what kind of information it can give a patient, even if the end result is we’re still going to take a watch-and-wait approach. That’s certainly very appropriate in many patients. But these prognostic tests can at least give them some additional information about what to expect.

And then often for patients who have had prior treatment some of these factors can help a physician decide what the best agents to choose are for the next course of treatment. And I think that is an area that is evolving as well as we gain more experience in using these combinations and knowing how patients respond to them based on some of this testing.

Andrew:
One of the questions I always thought about as to when to start treatment was, I didn’t want to have a treatment that would preclude me from a trial or just make me not a candidate for some newer, better therapy or combination that might come down the road.

Dr. Coutre:
For the majority of individuals when they’re first diagnosed, they’re at lower stage, and they don’t have symptoms. And there really still is not any justification for treating that patient unless they have significant symptoms or their disease moves on to a higher stage.

Fortunately - and a lot of individuals are interested in maybe being treated earlier - we’ll have these clinical trials available to them for looking at this early intervention issue. So I think there will be a lot of enthusiasm, not only among patients but among community oncologists for this kind of approach.

So that doesn’t shut the door to later treatment. When you’re starting to talk about treating patients who’ve had previous treatment, the way to look at it is for that individual, what’s the status of the disease, what’s the thing that is causing them the most problems? Is it problems with blood cells? Is it big lymph nodes? And then how can we use these different agents that we know about and have different activities in the best possible way to get the response that we’re looking for?

Andrew:
So that brings up clinical trials, and I think you were referring to this. I was in a clinical trial. I think it made a big difference for me in the FCR trial. And I’m sure you’d agree with me that if we can help you by being in trials that are appropriate for us, that really can change the face of the way we treat this illness.

Dr. Coutre:
Absolutely. I think when you look back and ask, “How did we make advances in treating this disease?” - it inevitably comes from clinical trials. A lot of people are scared of them. They think that they’re guinea pigs, but that’s really not the case. Our obligation is to design clinical trials that make sense, that people can be enthusiastic about participating in, that they feel they may benefit from. And time and time again, I think we’ve shown that we get answers that turn out to be important.

One could look back at those initial watch-and-wait trials. I would imagine that everybody wanted to be treated. It sort of makes sense. You’re diagnosed with cancer, wouldn’t you want to be treated for it? But what they showed us in that era was that many patients didn’t need to start therapy right away.

Now, our obligation is to demonstrate that these better drugs that we have can make a difference in some patients, can improve their quality of life and can help them live longer.

Andrew:
But that determination is best figured out as part of the clinical trial.

Dr. Coutre:That’s the only way, to be honest. It is the only way that you get those answers, to really be able to tell newly diagnosed patients, “This is what these trials showed us. This is why we’re doing what we’re doing. This is why we’re recommending this treatment for you.” It’s the only way that we really move the field forward.

Andrew:Dr. Steven Coutre, I know everyone joins me in applauding you for the work you and your colleagues are doing, both at Stanford and around the world. And I think it’s an exciting time. For those of us living with hope, we hope to be a very, very long-term condition. I know that’s what I’m hoping. The fact that you have better tests, we’re hopefully making smarter decisions, and you have more research moving forward. [It] sounds very encouraging. I’m sure you’d agree.

Dr. Coutre:
Definitely. It’s a very exciting time right now, I think, to know that we really have more options in treating patients. We are smarter about how we choose how to treat individuals. And I think equally important we can give more information to patients. We can give patients hope that we’re making these steps, we’re moving things forward.

Andrew:Well, thank you so much. Our guest has been Dr. Steven Coutre from the Comprehensive Cancer Center at Stanford University in Palo Alto, California.

I’m Andrew Schorr. From all of us at HealthTalk, we wish you and your family the best of health.

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